Does the Dose Make the Poison?

Randomized clinical trials (RCTs) are performed to provide unbiased assessment of the risks versus benefits of therapeutic and chemopreventive medications. Recently, two highly publicized RCTs noted increases in the risk of adverse cardiovascular outcomes with intake of well-known selective COX-2-inhibiting agents (rofecoxib and celecoxib) (“Gaps in the safety net,” J. Couzin, News Focus, 14 Jan., p. [196][1]). These studies were designed to assess chemopreventive effects of fixed doses of drugs against the recurrence of colonic polyps. Dosages of both rofecoxib (Vioxx) and celecoxib (Celebrex) administered in these RCTs were above the standard recommended doses (8 and 16 times, respectively, the typical dose when used in the treatment of arthritis). The nature of the double-blinded experimental design for these RCTs did not allow for adjustment of dose according to body size as recommended by the drug manufacturers. Because the therapeutic window of smaller individuals is usually reduced, their dose should be lowered and safety tolerance checked by measuring individual blood levels. Experimental designs of clinical trials should embellish rather than ignore two golden rules of medicine: The dose makes the poison and first do no harm. [1]: /lookup/doi/10.1126/science.307.5707.196